IJC

International Journal of Cancer

Short Report
Is human herpesvirus 8 infection more common in men than
in women? Systematic review and meta-analysis
Lorin Begre1*, Eliane Rohner1*, Sam M. Mbulaiteye2, Matthias Egger1,3 and Julia Bohlius1
1
Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
2
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
3
Centre for Infectious Disease Epidemiology & Research, School of Public Health & Family Medicine, University of Cape Town, Cape Town, South Africa

All forms of Kaposi sarcoma (KS) are more common in men than in women. It is unknown if this is due to a higher prevalence

Cancer Epidemiology
of human herpesvirus 8 (HHV-8), the underlying cause of KS, in men compared to women. We did a systematic review and
meta-analysis to examine the association between HHV-8 seropositivity and gender in the general population. Studies in
selected populations like for example, blood donors, hospital patients and men who have sex with men were excluded. We
searched Medline and Embase from January 1994 to February 2015. We included observational studies that recruited partici-
pants from the general population and reported HHV-8 seroprevalence for men and women or boys and girls. We used
random-effects meta-analysis to pool odds ratios (OR) of the association between HHV-8 and gender. We used meta-
regression to identify effect modifiers, including age, geographical region and type of HHV-8 antibody test. We included 22
studies, with 36,175 participants. Men from sub-Saharan Africa (SSA) [OR 1.21, 95% confidence interval (CI) 1.09–1.34], but
not men from elsewhere (OR 0.94, 95% CI 0.83–1.06), were more likely to be HHV-8 seropositive than women (p value for
interaction 5 0.010). There was no difference in HHV-8 seroprevalence between boys and girls from SSA (OR 0.90, 95% CI
0.72–1.13). The type of HHV-8 assay did not affect the overall results. A higher HHV-8 seroprevalence in men than women in
SSA may partially explain why men have a higher KS risk in this region.

Background
All forms of Kaposi sarcoma (KS) are more common in men
than in women; in children the male predominance is less
pronounced.1–4 Several direct and indirect mechanisms have
been suggested to explain the male predominance in KS. Sex
hormones may impact KS tumorigenesis although hormone
receptors were not found in KS tissue.5 Gender differences in
the susceptibility and immunological control of human her-
pesvirus 8 (HHV-8),6,7 a necessary but not sufficient infec-
tious cause of KS, may also contribute to the higher risk of
developing KS in men compared to women. A correlation
between higher HHV-8 seroprevalence and increased KS risk
has been shown in men who have sex with men (MSM).8
However, in heterosexual people it is not clear whether
HHV-8 seroprevalence is higher in men than in women and
could, therefore, explain the observed male predominance in
KS risk, particularly among adults. Several studies have
reported HHV-8 seroprevalence in men and women and

Key words: human herpesvirus 8, Kaposi sarcoma, seroprevalence, gender, meta-analysis

Abbreviations: CI: confidence interval; DNA: deoxyribonucleic acid; EIA: enzyme immunoassay; E.R.: Eliane Rohner; HHV-8: human
herpesvirus 8; HIV: human immunodeficiency virus; IFA: immunofluorescent assay; IQR: interquartile range; J.B.: Julia Bohlius; L.B.:
Lorin Begre; MSM: men who have sex with men; NA: not applicable; NR: not reported; N.W.: Natascha Wyss; OR: Odds ratio; PCR:
polymerase chain reaction; SSA: sub-Saharan Africa; STD: sexually transmitted disease; USA: United States of America; WB: western
blot; Z.H.: Zina Heg
Additional Supporting Information may be found in the online version of this article.
*L.B. and E.R. contributed equally to this work.
This work was presented at the 18th International Workshop on KSHV and Related Agents; June 30 – July 3, 2015; Miami, FL.
Grant sponsor: National Institute of Allergy and Infectious Diseases of the National Institutes of Health; Grant number: U01AI069924 to
M.E.; Grant sponsor: National Cancer Institute; Grant number: 5U01A1069924-05 to M.E.; Grant sponsor: Swiss National Science
Foundation; Grant number: Ambizione-PROSPER PZ00P3_160407 to J.B.
DOI: 10.1002/ijc.30129
History: Received 4 Dec 2015; Accepted 16 Mar 2016; Online 7 Apr 2016
Correspondence to: Julia Bohlius, MD, Institute of Social and Preventive Medicine (ISPM), University of Bern, Finkenhubelweg 11, CH-
3012 Bern, Switzerland, Tel.: 141 31 631 35 23, Fax: 141 31 631 35 20, E-mail: julia.bohlius@ispm.unibe.ch

Int. J. Cancer: 00, 00–00 (2016) V

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 2 HHV-8 infection in men and women
What’s new?
All forms of Kaposi sarcoma are more common in men than in women but the association of gender with human herpesvirus
8 (HHV8) status is less clear. In this meta-analysis of existing data, the authors found that men from sub-Saharan Africa,
where HHV-8 is endemic, were more likely to be HHV-8 seropositive than women. This association was only found in sub-
Saharan Africa and did not apply to boys in the same region, raising the question of sexual transmission and hormonal status
as additional factors in Kaposi sarcoma development.
boys and girls in different regions of the world. However, few
studies were designed to specifically assess the association
between gender and HHV-8 seropositivity and their findings
have been conflicting.9,10
We did a systematic literature review and meta-analysis to
examine whether HHV-8 seroprevalence is higher in men
Cancer Epidemiology
than in women. Understanding gender disparities is essential
to ultimately develop public health interventions to reduce
HHV-8 and KS incidence. We estimated the association
between HHV-8 seropositivity and gender in children and
adults from the general population, and examined reasons
for heterogeneous results between studies.
Methods
Eligibility criteria
We included HHV-8 seroepidemiological studies that recruited
participants from a general population in any region of the
world. HHV-8 seropositivity was used as a surrogate marker of
current or past infection. We defined a general population as a
representative sample of a population residing in a well-
defined geographical region. Thus, studies done in blood
donors, hospital-based studies or studies in selected popula-
tions like MSM, patients with solid organ transplantation,
HIV-positive individuals, persons who inject drugs and prison-
ers were excluded. We included children in developing coun-
tries who were enrolled during vaccination programs because
such programs are offered routinely to the general popula-
tion.11 We included studies that reported data on HHV-8 sero-
prevalence for men and women or boys and girls; or odds
ratios (ORs) of the association between gender and HHV-8
seroprevalence; irrespective of whether this was the main out-
come of the study or not. Studies which did not report HHV-8
data separately for children and adults were excluded. For pub-
lications that included both children and adults, we treated the
results for children and adults as separate studies. If a study
population included >80% adults (arbitrary cut-off), we con-
sidered it as an adult population study. For each study we used
the age cut-off for differentiation between childhood and adult-
hood as defined in the respective publication. We included
studies that gave male and female study participants the same
type of HHV-8 test [e.g., enzyme immunoassay (EIA), immu-
nofluorescent assay (IFA)] and antigens (e.g., ORF73, K8.1).
Literature search
We searched MEDLINE and EMBASE, without language
restrictions, for published reports from 01/1994 to 02/2015
using an electronic search strategy previously described by
Rohner et al.12 We screened reference lists of relevant
reviews, and searched the internet for additional material.
We examined abstracts from the following conferences: the
annual meeting of the American Society of Clinical Oncol-
ogy, the Conference on Retroviruses and Opportunistic Infec-
tions and the International Conference on Malignancies in
AIDS and Other Acquired Immunodeficiencies since 2008.
We screened titles and abstracts of all retrieved references,
and reviewed the full-text of potentially eligible articles. We
only excluded articles based on titles and abstracts if the
studies were either clearly done in selected, non-eligible pop-
ulations or if HHV-8 seroprevalence was not measured at all.
For all other studies the full texts including tables and figures
were reviewed to assess eligibility. Four reviewers [Eliane
Rohner (E.R.), Natascha Wyss (N.W.), Zina Heg (Z.H.) and
Lorin Begre (L.B.)] assessed whether the identified articles
reported data on HHV-8 seroprevalence and thereafter two
reviewers (L.B., E.R.) assessed eligibility specifically for the
current systematic review. In studies where the primary
reviewers did not agree, they consulted an additional reviewer
[Julia Bohlius (J.B.)].
Data extraction
Two reviewers (L.B., E.R.) extracted data from the articles
using a standardized form. The extracted data included the
study objectives, design and sampling strategy. Participant
characteristics such as age, socioeconomic status, sexual activ-
ity, HIV status and co-infections, when reported, were col-
lected. We also recorded the type of tests (EIA, IFA) and
antigens (latent, lytic) used to detect antibodies against
HHV-8. We recorded outcome data on HHV-8 seropreva-
lence separately for male and female study participants, as
well as the unadjusted and adjusted ORs of the association
between HHV-8 seropositivity and gender, and the potential
confounders for which the authors had adjusted. Two
reviewers (L.B., E.R.) entered the extracted data in duplicate
into an electronic database (Epidata version 3.1, The EpiData
Association, Odense, Denmark).
Statistical analyses
We used random-effects models to combine unadjusted ORs
of the association between gender and HHV-8 seropositivity.
For studies that did not report an OR, we calculated unad-
justed ORs based on extracted HHV-8 seroprevalence data. If
studies used different HHV-8 testing strategies, we chose EIA
Int. J. Cancer: 00, 00–00 (2016) V
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  et al.
Begre 3

Cancer Epidemiology
Figure 1. Association between HHV-8 seropositivity and gender in children and adults from sub-Saharan Africa and other regions. The
blocks and horizontal lines represent the odds ratios (OR) of the association between HHV-8 seropositivity and gender with their 95% confi-
dence intervals (CI) for each study. The center of the diamonds is the pooled point estimate of the studies included in each population
group, and the width of the diamonds represents the 95% CI of the pooled OR. p: p values from meta-regression analysis.
[Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

over IFA and lytic antigens over latent antigens, combined
tests over a single test, and algorithms where only one test
had to be positive over algorithms where all tests had to be
positive. We assessed between-study heterogeneity using I2-
statistics.13 We stratified main analyses by region and age
and used univariable and bivariable meta-regression analyses
to explore sources of between-study heterogeneity.14 We con-
sidered the following variables: age (children, adults); geo-
graphical region [sub-Saharan Africa (SSA), other regions];
ethnicity [>80% Black, >80% Asian (arbitrary cut-offs), vari-
ous ethnicities/unclear]; country income level, as defined by
the World Bank (low, middle, high income level);15 country
level HIV prevalence (<5%, 5–15%, >15%);16,17 study site
(rural, urban); HHV-8 test (EIA, IFA) and antigen (lytic,
latent) and, study size (number of study participants: < 500,
500–999, 1,000–1,999,  2,000). For studies conducted in
SSA, we assumed that participants were mainly black, if not
otherwise stated. In sensitivity analyses, we used fixed-effects
instead of random-effects meta-analysis; excluded studies for
which the number of analyzed male and female participants
was not reported; chose outcomes based on latent antigens
over lytic antigens, and outcomes based on IFA over EIA.
Where available, we also compared adjusted and unadjusted
study results and performed analyses using adjusted ORs. We
did all analyses in Stata version 13.1 (StataCorp LP, College
Station, TX).
Results
Selection of studies
We identified 4,140 references through the database searches,
including 3,037 unique references. We excluded 1,686 irrele-
vant references based on titles and abstracts, and assessed the
full texts of the remaining 1,351 articles. After full text assess-
ment, 1,331 references were excluded (see Supporting Infor-
mation Appendix Figure 1). Common reasons for excluding
references were that studies were not done in general popula-
tions (304 references), that references were reviews, book
chapters and editorials rather than original research (291
references), that examinations were done in samples other
than blood (189 references), and that HHV-8 seroprevalence
was not reported separately by gender (157 references). Three
additional studies were excluded because they did not report
HHV-8 seroprevalence data for children and adults

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 4 HHV-8 infection in men and women
separately.18–20 Thus, 17 publications reporting a total of 22
relevant studies in 36,175 children and adults were
included.21–37
Characteristics of included studies
Studies were done in 10 different countries: Cameroon, South
Africa, Tanzania, Uganda, Egypt, China, French Guiana,
United States, Italy and Sweden, see Table 1. The median
number of participants per study was 706 [interquartile range
(IQR) 427–1,477]. Nine (41%) studies were conducted in
children, and 13 (59%) in adults. Age cut-offs for differentia-
tion between childhood and adulthood varied between studies
and ranged from 14 to 19 years. Thirteen (59%) studies
mainly included black participants, two (9%) studies mainly
included Asian participants, and seven (32%) studies were
Cancer Epidemiology
done in populations with various or unclear ethnicities. The
primary objectives of the included studies were to study
HHV-8 seroprevalence (16 studies), risk factors for HHV-8
infection (12 studies) and HHV-8 transmission (7 studies).
In nine studies (41%), blood samples were collected specifi-
cally for the HHV-8 study whereas in 13 (59%) the samples
were originally collected for other purposes. Thirteen studies
(59%) used EIA only; seven (32%) used IFA only; one study
used IFA and Western Blot (WB); and one study used both
EIA and IFA. Fourteen studies (64%) tested for lytic antigens
only, and eight (36%) tested for latent and lytic antigens.
One study from Uganda37 and one study from the United
States26 reported data on the proportion of included MSM.
In these two studies, the proportion of MSM in men was
<2%. Nine studies (41%) reported HIV prevalence in their
study population, and HIV prevalence ranged between 0 and
39%. Adjusted ORs were reported for seven studies (32%).
Studies adjusted for different factors, including age, residence,
ethnicity, marital status and education (Table 1).
Main findings and meta-regression analyses
The main analysis, stratified by geographical region and age,
is presented in Figure 1 and Table 2. Overall, there was no
association between gender and HHV-8 seropositivity [OR
1.01, 95% confidence interval (CI) 0.91–1.11]. Heterogeneity
between studies was moderate (I2 5 44%) but statistically sig-
nificant (p 5 0.014). In SSA, male gender was associated with
HHV-8 seropositivity in adults (OR 1.21, 95% CI 1.09–1.34)
but not in children (OR 0.90, 95% CI 0.72–1.13; p value for
interaction 5 0.030). Outside SSA, male gender was not asso-
ciated with HHV-8 seropositivity in adults (OR 0.94, 95% CI
0.83–1.06). There was some evidence for a negative associa-
tion between male gender and HHV-8 seropositivity in chil-
dren (OR 0.68, 95% CI 0.49–0.94) but the difference between
adults and children was not statistically significant (p value
for interaction 5 0.098). Comparing the HHV-8/gender asso-
ciations between regions (SSA vs. outside SSA), the difference
was statistically significant in adults (p 5 0.010), but not in
children (p 5 0.189). In bivariable meta-regression, the inter-
action of the HHV-8/gender association with age (children
vs. adults) and region (SSA vs. outside SSA) remained statisti-
cally significant (p-values for interaction for age 5 0.002, for
region 5 0.002).
There was some evidence for an interaction of the associa-
tion between HHV-8 and gender with country income level
and country HIV prevalence; however, the results did not show
a dose-response relationship, see Table 2. Study size, type of
HHV-8 test or the HHV-8 antigen tested were not related to
HHV-8/gender associations. For study site and ethnicity, the
number of studies included in the meta-regression was too
small to allow solid conclusions. Within the four studies that
reported separate results for lytic and latent antigens there was
no evidence for an interaction of type of antigen tested with
the association between HHV-8 and gender (lytic antigens
pooled OR 0.87, 95% CI 0.71–1.06; latent antigens OR 1.08,
95% CI 0.89–1.32, p value for interaction 5 0.226).
Sensitivity analyses
Results were similar when repeating analyses using fixed-
effects models instead of random-effects models, and when
using results based on IFA and latent antigens. Likewise, the
results were similar when excluding studies for which the
number of analyzed male and female participants were not
reported and when using adjusted rather than unadjusted
estimates (see Supporting Information Appendix Tables 1
and 2).
Discussion
This comprehensive systematic review and meta-analysis of
the association between HHV-8 seropositivity and gender
showed that men in SSA but not men from other regions
were more likely to be HHV-8 seropositive than women.
Interestingly, in SSA the difference between genders was evi-
dent in adults but not in children, indicating that the inci-
dence of new HHV-8 infections may be higher in men than
in women in early adulthood but not in childhood.
This systematic review and meta-analysis has several
strengths. It is the first meta-analysis to explore the associa-
tion between HHV-8 seropositivity and gender in children
and adults from general populations in many different coun-
tries and regions. We restricted our analyses to studies that
recruited participants from the general population to mini-
mize selection and other biases associated with special popu-
lations, such as blood donors or people attending specialized
clinics.
We excluded studies conducted in MSM, since they have
higher HHV-8 seroprevalence than heterosexual men, and
tried to assess the proportion of MSM in the included stud-
ies. Unfortunately, only two studies26,37 reported the propor-
tion of MSM. In these studies, the proportion of MSM was
very low (<2%), but it is likely that due to stigma associated
with homosexuality MSM behavior was underreported, espe-
cially in Africa.38 We can, therefore, not exclude that MSM
may have contributed to a higher HHV-8 seroprevalence in
men compared to women in SSA. Conversely, HIV infection
Int. J. Cancer: 00, 00–00 (2016) V
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 Table 1. Characteristics of included studies
HHV-8
Begre

seroprevalence
(%) Odds ratio (95% confidence interval)4
 et al.

HHV-8 test MSM

Study and antigen Sample HIV1 in men
Author year Country period used size (%) (%) Males Females Unadjusted Adjusted
Sub-Saharan Africa, adults
Biryahwaho 2010 Uganda 2004–2005 EIA lytic 2,681 5.7 NR 57.52 53.72 NR 1.22 (1.03–1.45)5
1
Butler 2011 Uganda 2002 EIA lytic 1,477 6.3 NR 42.9 37.6 1.3 (1.02–1.5) 1.3 (1.02–1.6)6
Malope 2008 South Africa 2001 EIA latent & lytic 1,146 38.8 NR 47.5 46.0 1.1 (0.8–1.4) NR

Int. J. Cancer: 00, 00–00 (2016) V

Mbulaiteye 20031 Tanzania 1985 EIA lytic 361 NR NR 88.4 79.0 NR NR
Plancoulaine 20041 Cameroon 1998-NR IFA lytic 299 NR NR 78.43 72.13 NR NR

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Wawer 2001 Uganda 1994–1995 IFA & WB, 522 14.6 <0.5 42.7 35.0 1.38 (1.0–2.0) 1.33 (0.88–2.02)7
latent & lytic
Sub-Saharan Africa, children
Butler 2009 South Africa 2003 EIA & IFA lytic 427 6.4 NA NR NR 0.45 (0.18–1.1) 0.44 (0.18–1.1)8
1
Butler 2011 Uganda 2002 EIA lytic 1,382 <1 NA 27.3 26.6 1.04 (0.82–1.3) 1.0 (0.79–1.3)6
Dedicoat 2004 South Africa 2000–2002 EIA lytic 2,497 6.2 NA 10 13 NR NR
Mbulaiteye 20031 Tanzania 1985 EIA lytic 437 NR NA 58.7 54.5 1.18 (0.7–2.0) 1.1 (0.5–2.5)9
Plancoulaine 20041 Cameroon 1998-NR IFA lytic 309 NR NA 43.83 46.83 NR NR
Outside sub-Saharan Africa, adults
Engels 2007 United States 1988–1994 EIA lytic 13,894 NR 1.1 1.62 1.62 NR NR
Fu 2009 China 2007 EIA latent & lytic 2,228 NR NR 18.3 20.0 0.88 (0.71–1.09) NR
Mbulaiteye 20081 Egypt 1992 EIA lytic 730 NR NR 22.1 25.3 NR NR
Plancoulaine 20001 French Guiana 1994–1998 IFA latent & lytic 681 0 NR 18.83 19.13 NR NR
Serraino 2003 Italy 1998-NR IFA lytic 200 NR NR 9.0 6.0 NR NR
Tedeschi 2006 Sweden 1998–1999 IFA lytic 520 NR NR 15.03 13.83 NR NR
Wang 2011 China NR EIA latent & lytic 1,008 NR NR 22.3 23.8 0.91 (0.68–1.23) NR
Outside sub-Saharan Africa, children
Anderson 2008 United States 1988–1994 EIA latent & lytic 4,166 NR NA 1.22 1.62 0.7 (0.3–1.7) NR
1
Mbulaiteye 2008 Egypt 1992 EIA lytic 235 NR NA 9 20 0.4 (0.2–0.9) 0.4 (0.2–0.8)10
Perna 2000 Italy 1995–1997 IFA latent & lytic 319 0 NA 5.4 7.3 NR NR
Plancoulaine 20001 French Guiana 1994–1998 IFA latent & lytic 656 NR NA 6.53 8.23 NR NR
1
Separated into children and adult studies for analyses; 2weighted; 3calculated; 4as reported in the publication, reference group set to female for all studies. Adjustments: 5age, residence (urban vs
rural), region, marital status, education; 6age, ethnicity, household density, water source, number of HHV81 household members; 7age, marital status, education, occupation, sex partners, STDs;
8
age, HIV status, study site (rural vs urban); 9age, HHV-8 serostatus of relatives, HHV-8 serostatus of older sibling, elevation of village, 10schistosomiasis.
Abbreviations: EIA: enzyme immunoassay; HHV-8: human herpesvirus 8; IFA: immunofluorescent assay; MSM: men who have sex with men; NA: not applicable; NR: not reported; STDs: sexually
transmitted diseases; WB: western blot.
5

Cancer Epidemiology
 Cancer Epidemiology

Table 2. Association between HHV-8 seropositivity and gender (male vs. female), stratified analyses
Age Region
Adults Children SSA Outside SSA
N OR (95% CI) p N OR (95% CI) p N OR (95% CI) p N OR (95% CI) p
Overall 13 1.09 (0.98–1.20) 9 0.84 (0.70–1.01) 11 1.10 (0.96–1.27) 11 0.90 (0.80–1.01)
Region
Sub-Saharan Africa 6 1.21 (1.09–1.34) 0.010 5 0.90 (0.72–1.13) 0.189 – –
Outside SSA 7 0.94 (0.83–1.06) 4 0.68 (0.49–0.94) – –
Age
Adults – – 6 1.21 (1.09–1.34) 0.030 7 0.94 (0.83–1.06) 0.098
Children – – 5 0.90 (0.72–1.13) 4 0.68 (0.49–0.94)
Ethnicity
>80% Black 7 1.19 (1.08–1.32) 0.027 6 0.89 (0.73–1.09) – 11 1.10 (0.96–1.27) – 2 0.91 (0.66–1.26) 0.938
>80% Asian 2 0.90 (0.76–1.07) 0 – 0 – 2 0.90 (0.76–1.07)
Various ethnicities/unclear1 4 0.98 (0.81–1.19) 3 0.63 (0.43–0.94) 0 – 7 0.89 (0.73–1.08)
Country income level
Low 4 1.25 (1.10–1.43) 0.040 2 1.08 (0.88–1.32) 0.079 6 1.20 (1.08–1.33) 0.050 0 – 0.427
Middle 5 0.96 (0.84–1.09) 4 0.71 (0.54–0.92) 5 0.91 (0.70–1.18) 4 0.86 (0.72–1.02)
High 4 1.02 (0.84–1.25) 3 0.75 (0.52–1.07) 0 – 7 0.95 (0.80–1.13)
Country HIV prevalence
<5% 8 0.96 (0.85–1.08) 0.038 5 0.74 (0.57–0.97) 0.079 2 1.09 (0.70–1.70) 0.118 11 0.90 (0.80–1.01) –
5–15% 4 1.25 (1.10–1.43) 2 1.08 (0.88–1.32) 6 1.20 (1.08–1.33) 0 –
>15% 1 1.06 (0.83–1.35) 2 0.70 (0.51–0.98) 3 0.82 (0.58–1.17) 0 –
Study site
Rural 7 1.15 (0.95–1.38) 0.757 6 0.88 (0.71–1.09) 0.727 8 1.13 (0.93–1.37) 0.816 5 0.86 (0.72–1.03) 0.727
Urban 1 1.06 (0.83–1.35) 1 0.72 (0.29–1.79) 1 1.06 (0.83–1.35) 1 0.72 (0.29–1.79)
Mixed rural/urban1 5 1.05 (0.92–1.19) 2 0.65 (0.41–1.02) 2 0.81 (0.33–2.00) 5 0.94 (0.81–1.09)
Test used for HHV-8 detection
EIA 10 1.07 (0.95–1.19) 0.501 7 0.86 (0.71–1.05) 0.470 9 1.10 (0.95–1.26) 0.211 8 0.89 (0.79–1.00) 0.426
IFA 2 1.17 (0.75–1.82) 1 0.72 (0.29–1.79) 0 – 3 1.06 (0.71–1.58)
EIA and IFA 0 – 1 0.45 (0.18–1.11) 1 0.45 (0.18–1.11) 0 –

Int. J. Cancer: 00, 00–00 (2016) V

IFA and WB 1 1.38 (0.97–1.97) 0 – 1 1.38 (0.97–1.97) 0 –
HHV-8 infection in men and women

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  et al.
Begre 7

increases the risk of HHV-8 seropositivity,39 and in SSA

more women than men are HIV-infected.40 Higher HIV

Abbreviations: CI: confidence interval; EIA: enzyme immunoassay; HHV-8: human herpesvirus 8; HIV: human immunodeficiency virus; IFA: immunofluorescent assay; N: number of studies; OR: odds
0.630

0.755
prevalence in women could, therefore, counterbalance the
effect of unreported MSM behavior on HHV-8 seropreva-
p

lence. Although several studies included in this meta-analysis

Outside SSA

0.88 (0.75–1.03)
0.93 (0.78–1.10)

0.72 (0.35–1.49)
0.92 (0.74–1.14)

0.91 (0.78–1.07)
0.92 (0.68–1.23)
reported HIV prevalence in their study population, only one
OR (95% CI)

study adjusted the OR of the HHV-8/gender association for

HIV status.23 In this study, adjustment for HIV status did
not change the OR much. We found evidence that outside
SSA, boys were less likely to be HHV-8 seropositive than
girls. This finding might be spurious because it was based on
Region

4
7

3
4

3
1
few studies with small numbers of HHV-8 seropositive boys
and girls. Also, the observed association was not statistically
0.657

0.753

significantly different from adults outside SSA or children

p

from SSA. Most studies used different tests to determine

Cancer Epidemiology
HHV-8 seropositivity. This made direct comparison of
HHV-8 seroprevalence between studies difficult. However,
1.08 (0.91–1.28)
1.17 (0.91–1.51)

1.13 (0.79–1.63)
1.38 (0.97–1.97)

0.95 (0.61–1.46)
1.13 (0.99–1.28)
SSA

within each study the same test was used on males and
OR (95% CI)

females, and therefore, ORs of the association between HHV-

8 seropositivity and gender as relative measures should be
better comparable than HHV-8 seroprevalence. Indeed, in
sensitivity analyses we found no evidence for an effect of the
Table 2. Association between HHV-8 seropositivity and gender (male vs. female), stratified analyses (Continued)

type of HHV-8 assay on the overall results.

N

9
2

5
1

2
3

We observed that in SSA HHV-8 seroprevalence in the

0.605

0.788

general population was higher in men than women, but not

in boys compared to girls. This is in line with the male pre-
p

dominance in KS incidence and prevalence in this region,

0.85 (0.68–1.05)
0.73 (0.46–1.15)

0.76 (0.51–1.14)
0.78 (0.43–1.41)

0.75 (0.60–0.93)
1.04 (0.82–1.32)

which is mainly observed in adults and to a lesser extent in

Children

children.4 The higher HHV-8 seroprevalence in men from

OR (95% CI)

SSA indicates that men may be more susceptible to HHV-8

infection than women in this region. Both biological and
behavioral factors might contribute to the gender difference
in adults. Sex hormones influence immune cells and lead to
N

7
2

5
1

2
1

generally stronger immune responses in women compared to

Age

men.41 Therefore, it is plausible that reduced immune control

0.209

0.277

ratio; p: p-value for interaction; SSA: sub-Saharan Africa; WB: Western Blot.

of HHV-8 in men might result in more frequent reactivation

p

of HHV-8. A study from Uganda which showed that HHV-8

1.14 (1.02–1.28)

1.63 (1.12–2.38)
1.02 (0.86–1.21)

1.06 (0.85–1.33)

1.03 (0.86–1.22)
1.09 (0.92–1.30)

deoxyribonucleic acid (DNA) was more commonly detected

Adults

in men than women supports this hypothesis.42 However, we

OR (95% CI)

would have expected to observe this effect in adults from

regions outside SSA as well. The positive association of
HHV-8 seropositivity with male gender might also be
explained by heterosexual transmission with more sexual
N

contacts in men compared to women. Although, in one

9

3
4

3
3

study24 where the OR of the HHV-8/gender association was

Antigen used for HHV-8 detection

adjusted for number of sex partners, the adjusted and unad-

Excluded from test for interaction.

justed OR were very similar. Another potential explanation is

the notion that sexual transmission of HHV-8 could be—in
Number of participants

contrast to other sexually transmitted infections—more effi-

cient from women to men than from men to women.43
Latent and lytic

In conclusion, it remains unclear why we found a positive

1000–1999

association between male gender and HHV-8 seropositivity in

500–999

adults from SSA, but not in adults from other regions. More
2000
<500
Lytic

research on the causal pathway from HHV-8 infection to KS

and its association with gender is required to ultimately
1

Int. J. Cancer: 00, 00–00 (2016) V

C 2016 UICC
 8 HHV-8 infection in men and women
develop preventive measures against HHV-8 infection and sub-
sequent KS in men and women. Standards of HHV-8 testing
are needed to improve our ability to compare data from differ-
ent studies. In the meantime, our data indicate that in SSA a
higher HHV-8 seroprevalence in men may contribute to the
higher KS risk observed in men than in women.
References
1. Serraino D, Angeletti C, et al. Kaposi’s sarcoma
in transplant and HIV-infected patients: an epi-
demiologic study in Italy and France. Transplan-
tation 2005;80:1699–704.
2. Dal Maso L, Polesel J, Ascoli V, et al. Classic
Kaposi’s sarcoma in Italy, 1985-1998. Br J Cancer
2005;92:188–93.
Cancer Epidemiology
3. Tukei VJ, Kekitiinwa A, Beasley RP. Prevalence
and outcome of HIV-associated malignancies
among children. AIDS 2011;25:1789–93.
4. Matondo P. Kaposi’s sarcoma in Africa. Clin Der-
matol 1999;17:197–207.
5. Ziegler JL, Katongole-Mbidde E, Wabinga H,
et al. Absence of sex-hormone receptors in
Kaposi’s sarcoma. Lancet 1995;345:925
6. Klein SL. The effects of hormones on sex differ-
ences in infection: from genes to behavior. Neu-
rosci Biobehav Rev 2000;24:627–38.
7. Brown EE. A common genetic variant in
FCGR3A-V158F and risk of Kaposi sarcoma her-
pesvirus infection and classic Kaposi sarcoma.
Cancer Epidemiol Biomarkers Prev 2005;14:633–7.
8. Bhutani M, Polizzotto MN, Uldrick TS, et al. Kaposi
sarcoma-associated herpesvirus-associated malig-
nancies: epidemiology, pathogenesis, and advances
in treatment. Semin Oncol 2015;42:223–46.
9. Plancoulaine S, Abel L, van Beveren M, et al.
High titers of anti-human herpesvirus 8 antibod-
ies in elderly males in an endemic population.
J Natl Cancer Inst 2002;94:1333–5.
10. Fu B, Yang R, Xia F, et al. Gender differences in
Kaposi’s sarcoma-associated herpesvirus infection
in a population with schistosomiasis in rural
China. Jpn J Infect Dis 2012;65:350–3.
11. Harris JB, Gacic-Dobo M, Eggers R, et al. Global
routine vaccination coverage, 2013. MMWR
Morb Mortal Wkly Rep 2014;63:1055–8.
12. Rohner E, Wyss N, Trelle S, et al. HHV-8 sero-
prevalence: a global view. Syst Rev 2014;3:11
13. Higgins JPT, Thompson SG. Quantifying hetero-
geneity in a meta-analysis. Stat Med 2002;21:
1539–58.
14. Sterne JA, J€uni P, Schulz KF, et al. Statistical
methods for assessing the influence of study char-
acteristics on treatment effects in “meta-
epidemiological” research. Stat Med 2002;21:
1513–24.
15. The World Bank. Country and Lending Groups.
[cited 2015 Sep 14]. Available at: http://data.
worldbank.org/about/country-and-lending-groups
16. UNAIDS. Countries. [cited 2016 Feb 17].
Available at: http://www.unaids.org/en/
regionscountries/countries
17. World Health Organization. Global Health
Observatory data repository. Prevalence of HIV
among adults aged 15 to 49 - Estimates by
country. [cited 2016 Feb 17]. Available at: http://
apps.who.int/gho/data/node.main.562?lang5en
Acknowledgements
We thank Natascha Wyss and Zina Heg for their contributions to the refer-
ence screening and Kali Tal for her editorial suggestions. This study was
done on behalf of The International epidemiologic Database to Evaluate
AIDS (IeDEA). The content is solely the responsibility of the authors and
does not necessarily represent the official views of the National Institutes of
Health. The authors have no conflicts of interest to declare.
18. Borges JD, Souza VA, Giambartolomei C, et al.
Transmission of human herpesvirus type 8 infec-
tion within families in american indigenous pop-
ulations from the Brazilian Amazon. J Infect Dis
2012;205:1869–76.
19. Cunha AM, Caterino-de-Araujo A, Costa SC,
et al. Increasing seroprevalence of Human herpes-
virus 8 (HHV-8) with age confirms HHV-8 ende-
micity in Amazon Amerindians from Brazil.
J Gen Virol 2005;86:2433–7.
20. Katano H, Iwasaki T, Baba N, et al. Identification
of antigenic proteins encoded by human herpes-
virus 8 and seroprevalence in the general popula-
tion and among patients with and without
Kaposi’s sarcoma. J Virol 2000;74:3478–85.
21. Anderson LA, Li Y, Graubard BI, et al. Human
herpesvirus 8 seroprevalence among children and
adolescents in the United States. Pediatr Infect
Dis J 2008;27:661–4.
22. Biryahwaho B, Dollard SC, Pfeiffer RM, et al. Sex
and geographic patterns of human herpesvirus 8
infection in a nationally representative
population-based sample in Uganda. J Infect Dis
2010;202:1347–53.
23. Butler LM, Dorsey G, Hladik W, et al. Kaposi
sarcoma-associated herpesvirus (KSHV) seropre-
valence in population-based samples of African
children: evidence for at least 2 patterns of KSHV
transmission. J Infect Dis 2009;200:430–8.
24. Butler LM, Were WA, Balinandi S, et al. Human
herpesvirus 8 infection in children and adults in
a population-based study in rural Uganda.
J Infect Dis 2011;203:625–34.
25. Dedicoat M, Newton R, Alkharsah KR, et al.
Mother-to-child transmission of human
herpesvirus-8 in South Africa. J Infect Dis 2004;
190:1068–75.
26. Engels EA, Atkinson JO, Graubard BI, et al. Risk
factors for human herpesvirus 8 infection among
adults in the United States and evidence for sex-
ual transmission. J Infect Dis 2007;196:199–207.
27. Fu B, Sun F, Li B, et al. Seroprevalence of Kapo-
si’s sarcoma-associated herpesvirus and risk fac-
tors in Xinjiang, China. J Med Virol 2009;81:
1422–31.
28. Malope BI, Macphail P, Mbisa G, et al. No evi-
dence of sexual transmission of Kaposi’s sarcoma
herpes virus in a heterosexual South African pop-
ulation. AIDS 2008;22:519–26.
29. Mbulaiteye SM, Pfeiffer RM, Whitby D, et al.
Human herpesvirus 8 infection within families in
rural Tanzania. J Infect Dis 2003;187:1780–5.
30. Mbulaiteye SM, Pfeiffer RM, Dolan B, et al. Sero-
prevalence and risk factors for human herpesvirus
8 infection, rural Egypt. Emerg Infect Dis 2008;14:
586–91.
31. Perna AM, Bonura F, Vitale F, et al. Antibodies
to human herpes virus type 8 (HHV8) in general
population and in individuals at risk for sexually
transmitted diseases in Western Sicily. Int J Epi-
demiol 2000;29:175–9.
32. Plancoulaine S, Abel L, van Beveren M, et al.
Human herpesvirus 8 transmission from mother
to child and between siblings in an endemic pop-
ulation. Lancet 2000;356:1062–5.
33. Plancoulaine S, Abel L, Tregou€et D, et al. Respec-
tive roles of serological status and blood specific
antihuman herpesvirus 8 antibody levels in
human herpesvirus 8 intrafamilial transmission in
a highly endemic area. Cancer Res 2004;64:8782–
7.
34. Serraino D, Corona RM, Giuliani M, et al. Infec-
tion with human herpesvirus type 8 and Kaposi’s
sarcoma in a central Italian area formerly
endemic for malaria. Infection 2003;31:47–50.
35. Tedeschi R, Bidoli E, Agren A, et al. Epidemiol-
ogy of Kaposi’s Sarcoma herpesvirus (HHV8) in
Vasterbotten County, Sweden. J Med Virol 2006;
78:372–8.
36. Wang H, Liu J, Dilimulati, et al. Seroprevalence
and risk factors of Kaposi’s sarcoma-associated
herpesvirus infection among the general Uygur
population from south and north region of Xin-
jiang, China. Virol J 2011;8:539.
37. Wawer MJ, Eng SM, Serwadda D, et al. Preva-
lence of Kaposi sarcoma-associated herpesvirus
compared with selected sexually transmitted dis-
eases in adolescents and young adults in rural
Rakai District, Uganda. Sex Transm Dis 2001;28:
77–81.
38. Diversity in Human Sexuality. Implications for
Policy in Africa. [cited 2015 Nov 30]. Available
at: http://www.assaf.co.za/wp-content/uploads/
2015/06/8-June-Diversity-in-human-sexuality1.pdf
39. Rohner E, Wyss N, Heg Z, et al. HIV and human
herpesvirus 8 co-infection across the globe: Sys-
tematic review and meta-analysis. Int J Cancer
2016;138:45–54.
40. UNAIDS Fact Sheet 2015 [cited 2015 Dec 1].
Available at: http://www.unaids.org/sites/default/
files/media_asset/20150901_FactSheet_2015_en.
pdf
41. Oertelt-Prigione S. The influence of sex and gen-
der on the immune response. Autoimmun Rev
2012;11:A479–85.
42. Shebl FM, Emmanuel B, Bunts L, et al. Popula-
tion-based assessment of kaposi sarcoma-
associated herpesvirus DNA in plasma among
Ugandans. J Med Virol 2013;85:1602–10.
43. Dupuy A, Schulz T, Chevret S, et al. Asymmetri-
cal transmission of human herpesvirus 8 among
spouses of patients with Kaposi sarcoma. Br J
Dermatol 2009;160:540–5.
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C 2016 UICC